Programmed Cell Death 1 or PD-1 (also referred to as PDCD1) is a 50 to 55 kDa type I transmembrane receptor of the CD28 superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands and is suggested to play a role in the maintenance of self-tolerance.
PD-1 antigen relates to almost every aspect of immune responses including autoimmunity, tumor immunity, infectious immunity, transplantation immunity, allergy and immunological privilege.
PD-1 is expressed on the surface of activated T cells, B cells, and macrophages, (Y. Agata et al., International Immunology vol. 8, No. 5 p 765-772, 1996) suggesting that compared to CTLA-4 that also plays an important regulatory role in the immune system, PD-1 more broadly negatively regulates immune responses.
In general, a need exists to provide safe and effective therapeutic methods for immune disorders such as, for example, autoimmune diseases, inflammatory disorders, allergies, transplant rejection, cancer, immune deficiency, and other immune system-related disorders. Modulation of the immune responses involved in these disorders can be accomplished by manipulation of the PD-1 pathway.
PD-1 has two ligands, PD-L1 (Programmed Death Ligand for PDCD1 L1 or B7-H1) and PD-L2 (Programmed Death Ligand 2 or PDCD1 L2 or B7-DC), which are members of the B7 family ligands.
In one approach, blocking the interaction of PD-1 as well as its ligand (PD-L1, PD-L2 or both) may provide an effective way for tumor and viral immunotherapy.
U.S. Pat. No. 5,629,204 and U.S. Pat. No. 5,698,520 relate to a membrane protein related to human PD-1 and DNA encoding the said protein, and indicates that PD-1 protein may be useful for the treatment of various infections, immunological depression or acceleration, or tumors etc.
U.S. Pat. No. 7,595,048 and US 2011/0081341 relate to immunopotentiation characterized by inhibiting immunosuppressive signals induced by PD-1, PD-L1 or PD-L2, compositions for cancer or infection treatment, and therapies that use them.
Several big pharmaceutical companies are pitting their PD-1 antibodies against each other in a race to be first to market. Here are 3 monoclonal antibodies such as Merck's Lambrolizumab (MK-3475) which is a humanized monoclonal IgG4 antibody that acts against PD-1, Bristol-Myers Squibb's Nivolumab (BMS-936558) which is fully anti human PD-1 antibody and Roche Genentech's MPDL3280A which doesn't block PD-1, but rather blocks PD-L1.
However, more potent and safe compound targeting PD-1 is strongly desired.
Virus-like particles (VLPs) are multiprotein structures that mimic the organization and conformation of authentic native viruses but lack the viral genome, potentially yielding safer and cheaper vaccine candidates. A handful of prophylactic VLP-based vaccines is currently commercialized worldwide: GlaxoSmithKline's Engerix® (hepatitis B virus) and Cervarix® (human papillomavirus), and Merck and Co., Inc.'s Recombivax HB® (hepatitis B virus) and Gardasil® (human papillomavirus) are some examples. Other VLP-based vaccine candidates are in clinical trials or undergoing preclinical evaluation, such as, influenza virus, parvovirus, Norwalk and various chimeric VLPs. Many others are still restricted to small-scale fundamental research, despite their success in preclinical tests. The implications of large-scale VLP production are discussed in the context of process control, monitorization and optimization. The main up- and down-stream technical challenges are identified and discussed accordingly. Successful VLP-based vaccine blockbusters are briefly presented concomitantly with the latest results from clinical trials and the recent developments in chimeric VLP-based technology for either therapeutic or prophylactic vaccination (Expert Rev. Vaccines 9(10), 1149-1176, 2010).
Chikungunya virus (CHIKV) has infected millions of people in Africa, Europe and Asia since this alphavirus reemerged from Kenya in 2004. The severity of the disease and the spread of this epidemic virus present a serious public health threat in the absence of vaccines or antiviral therapies. It is reported that a VLP vaccine for epidemic Chikungunya virus protects non-human primates against infection (Nat Med. 2010 March; 16(3): 334-338). US patent publication No. 2012/0003266 discloses a virus-like particle (VLP) comprising one or more Chikungunya virus structural proteins which is useful for formulating a vaccine or antigenic composition for Chikungunya that induces immunity to an infection or at least one symptom thereof. WO2012/106356 discloses modified alphavirus or flavivirus virus-like particles (VLPs) and methods for enhancing production of modified VLPs for use in the prevention or treatment of alphavirus and flavivirus-mediated diseases. (these cited references are herein incorporated by reference).